Recognition and management of phaeochromocytoma

ENDOCRINOLOGY

© 2005 The Medicine Publishing Company Ltd336ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:10

Phaeochromocytomas are catecholamine-containing tumours of chromaffin cells. They are pharmacologically volatile and poten-tially lethal. Phaeochromocytomas occur wherever chromaffin tissue is located: 90% are found in the adrenal medulla, and the remainder in other sites including the paraganglia cells of the sympathetic nervous system and the organ of Zuckerkandl. 10% of phaeochromocytomas are extra-adrenal, 10% are bilateral and 10% are metastatic. These tumours are important to the anaesthetist because 25–50% of hospital deaths in patients with phaeochromo-cytoma occur during induction of anaesthesia or during operative procedures for other causes.

The sympathetic nervous systemThe sympathetic nervous system comprises the sympathetic chain, a number of peripheral plexuses and the adrenal medulla. The axons of the sympathetic preganglionic neurons leave the spinal cord with the ventral roots of T1–L2. They pass via the white rami communicantes to the paravertebral sympathetic chain where most of them end on the cell bodies of the postganglionic neu-rons. This sympathetic chain lies posterior to the aorta on either side of the thoracic column and the neurotransmitter at the ends of these preganglionic axons is acetylcholine. The axons of some of the postganglionic neurons pass to the viscera in the various sympathetic nerves (predominantly noradrenergic). Others re-enter the spinal nerves via the grey rami communicantes from the sym-pathetic chain and are distributed to autonomic effectors in the areas supplied by these spinal nerves. Some preganglionic neurons pass through the sympathetic chain without synapsing and form the splanchic nerves that extend to, and terminate in, the outlying prevertebral ganglia. Sympathetic preganglionic fibres also extend to the adrenal medullae. Developmentally, the adrenal medullae are modified sympathetic ganglia derived from chromaffin cells. When stimulated by these sympathetic cholinergic preganglionic neurons the adrenal medullae release a mixture of catecholamine hormones: about 80% adrenaline, 20% noradrenaline and a trace amount of dopamine.

Recognition and management of phaeochromocytomaSimon Lewis

Andrew K McIndoe

Simon Lewis is a Specialist Registrar in Anaesthesia on the Bristol

Rotation. He has an interest in vascular anaesthesia.

Andrew K McIndoe is Consultant Anaesthetist and Senior Clinical Lecturer

in the Sir Humphry Davy Department of Anaesthesia, Bristol Royal

Infirmary, UK. He is also the Director of Research and Education at the

Bristol Medical Simulation Centre where he has developed a specific

interest in human factors and crisis management.

ENDOCRINOLOGY


Catecholamine synthesis and metabolismCatecholamines are formed by the hydroxylation and decarboxy-lation of the amino acid tyrosine. Some of the tyrosine is formed from phenylalanine, but most is of dietary origin. Within the chro-maffin cell, tyrosine is hydroxylated to dopa which is transported to the nerve terminals. Dopa is decarboxylated to dopamine and accumulates in granulated vesicles in the nerve terminal. The membranes of these vesicles contain dopamine β-hydroxylase, which converts dopamine to noradrenaline (Figure 1). In the adrenal medulla, noradrenaline is converted to adrenaline by phenylethanolamine-N-methyltransferase. After release from the adrenal medulla the catecholamines are eliminated rapidly. Up to 90% of the noradrenaline released at the synapse is taken up by the presynaptic nerve endings (uptake 1). This process is blocked by cocaine, tricyclic antidepressants, metaraminol or phenothiazines (Figure 2). Although circulating catecholamines can be metabolized by this route (uptake 1), 70% of adrenaline is methoxylated by catechol-O-methyltransferase (COMT) in the liver and kidney (uptake 2).

PredispositionPhaeochromocytomas are classified as sporadic or familial in origin. Most are sporadic and benign. Familial conditions asso-ciated with phaeochromocytoma include multiple endocrine neoplasia (MEN) IIA and IIB, von Hippel–Lindau disease, neuro-fibromatosis type I (von Recklinghausen disease), tuberose scle-rosis and Sturge–Weber syndrome.

PresentationHypertension is the most common sign in patients presenting with phaeochromocytoma; however, only 0.04% of all hypertensive patients have a phaeochromocytoma. The three most common symptoms are headache, sweating and palpitations. Presentation depends on the pattern of catecholamine secretion by the tumour. Those secreting predominantly noradrenaline (80–90%) present with sustained hypertension, headaches and slow, thudding palpitations. Those with adrenaline-secreting tumours (10–17%) present with the paroxysmal symptoms of palpitations, trembling, sweating and anxiety. Other less common features include nausea and vomiting (dopamine secretors), cerebrovascular accident and cardiac failure. Symptoms may be precipitated by postural changes, increases in intra-abdominal pressure, trauma, exercise or certain medications. Phaeochromocytoma multisystem crisis is an unusual and life-threatening complication that comprises multi-organ failure, hyperpyrexia, encephalopathy and hypertension or hypotension. Prompt diagnosis and aggressive medical and supportive therapy are required.

DiagnosisThe definitive diagnosis of phaeochromocytoma relies on the demonstration of an excessive inappropriate production of catechol-amines. This is difficult to measure because catecholamines are rapidly reabsorbed or metabolized following release. Elevated levels of plasma and urinary catecholamines are the most sensitive

Catecholamine synthesis and elimination

Facilitation Inhibition

Synthesis

Tyrosine hydroxylase Metyrosine

Dopamine

Norepinephrine

Storage

Dopamine β-hydroxylase Reserpine

Guanethidine

Release

Angiotensin α2-receptor stimulation

Ephedrine Magnesium

Amphetamine Guanethidine

Bretylium

Reuptake

Norepinephrine Cocaine

Metaraminol

Tricyclic antidepressants

Phenothiazines

Monoamine oxidase breakdown (MAO)

Progesterone Monoamine oxidase inhibitors

Oestrogen

COMT breakdown Corticosteroids

Phenoxybenzamine

2

Catecholamine biochemistry

COMT, catechol-O-methyltransferase MAO, monoamine oxidase

HO

HOCOMT

MAO

COMT

COMT

MAO

MAO

C C

H H

H

HO COOHC

H

HH

NH2

HO

HO C C

OH H

H H

NH2

HO

HO C C

OH H CH3

H H

NH

CH3O

HO COOHC

OH

H

CH3O

Dopamine

Noradrenaline

Adrenaline

Homovanillic acid

Vanillylmandelic acid

Metanephrine

Normetanephrine

1

ENDOCRINOLOGY


method to confirm the diagnosis. Elevated levels of urinary vanillyl-mandelic acid are less sensitive. Plasma levels of the metabolites normetanephrine and metanephrine also have a high sensitivity. Biochemical testing can confirm the diagnosis in over 95% of patients. If the diagnosis cannot be confirmed, the clonidine sup-pression test can be used. Clonidine is an α2-agonist and usually causes a decrease in physiological release of noradrenaline from sympathethic nerve terminals by negative feedback inhibition. Lack of suppression is suggestive of a phaeochromocytoma in the absence of reuptake inhibitors (tricyclic antidepressants, cocaine, metaraminol, phenothiazines).

LocalizationCT and MRI provide accurate and consistent identification of most phaeochromocytomas. CT has a sensitivity of 93–100% for detecting adrenal tumours and 90% for extra-adrenal tumours (Figure 3). MRI is better at detecting extra-adrenal phaeochromo-cytomas. It is also the investigation of choice in pregnancy because it avoids exposure of the fetus to radiation. Both CT and MRI have poor specificity, but if there is doubt, nuclear imaging using 123I-metaiodobenzylguanidine (MIBG) scintigraphy enhances the ability to identify and localize the catecholamine source. MIBG is concentrated by the tumour’s uptake of precursor amines; the process takes 24–48 hours.

Preoperative managementExcision of the phaeochromocytoma can be undertaken safely only when pharmacological stability of the sympathetic nervous system has been achieved. The perioperative mortality decreased from 13–45% to 0–3% when preoperative α-adrenergic blockade was instigated and when it was recognized that these patients often had hypovolaemia preoperatively. The priorities are to ensure stable blood pressure, heart rate and restoration of a normal blood volume. Pharmacological control can be achieved by the interruption or antagonism of catecholamine synthesis, release or recep-tor action. The traditional approach is to institute α-adrenergic blockade and then to add β-adrenergic blockade if required. The use of β-adrenoceptor blockade alone can lead to hypertension owing to blockade of β2-induced vessel-wall relaxation, resulting in unopposed α-adrenoceptor vasoconstriction (Figure 4).

Phenoxybenzamine is considered by many to be the drug of choice for controlling blood pressure alterations and associated symptoms. It binds covalently to α1- and α2-adrenoceptors thereby blocking catecholamine-induced vasoconstriction and catechol-amine reuptake. Orthostatic hypotension and reflex tachycardia occur, the latter secondary to inhibition of presynaptic α2-adreno-ceptors, resulting in an increase in circulating catecholamines at the unopposed β-receptors. Therefore, adjuvant β-blockade is normally required to control the tachycardia. Preoperative control is good, but postoperatively patients remain sleepy (due to persistent cen-tral α2-adrenoceptor blockade) and may require large volumes of intravenous fluid to maintain blood pressure until the blockade has worn off. The effects of phenoxybenzamine dissipate over about 36 hours and patients usually stop taking the drug 24–48 hours before surgery. Selective α1-adrenoceptor antagonists offer several potential advantages compared with phenoxybenzamine. They do not produce reflex tachycardia (because the α2-adrenoceptors are not inhibited) and have a shorter duration of action, resulting in less postoperative hypotension. Preoperative β-blockade is unnecessary unless the patient has an adrenaline-secreting tumour. Doxazosin has a long duration of action and can be given in once-daily doses up to and including the eve of surgery. Prazosin and terazosin can also be considered, but require more frequent dosing. β-adrenergic antagonists are indicated for patients who have adrenaline-secreting tumours. They are contraindicated in the absence of established α-blockade because circulating catechol-amines would produce vasoconstriction without opposition by the vasodilating β2-receptors. The resulting hypertension can precipi-tate pulmonary oedema, which can be exacerbated by the nega-tive ionotropic effects of the β-blockade. Suitable options include atenolol and bisoprolol. Labetalol (a combined α- and β-blocker) can be used, but it has been reported to precipitate hypertensive crisis. α-methylparatyrosine competitively inhibits tyrosine hydroxy-lase, which is the rate-limiting step in catecholamine synthesis. By reducing the tumour’s catecholamine stores it decreases the ability of the phaeochromocytoma to react to stimulation. It can be used for patients with poor left ventricular function in whom β-blockade worsens cardiac performance and α-blockade leads to tachycardia. Roizen et al. have recommended the following criteria for optimal preoperative conditions:3 CT scan of large phaeochromocytoma (arrowed).

Adrenoreceptor effects

Receptor Principal effects

α1 Vasoconstriction, uterine contraction, increased

sweating, decreased insulin release, decreased

glucagon release

α2 Inhibition of further noradrenaline release

β1 Chronotropy, ionotropy, arrhythmogenicity, renin

secretion

β2 Smooth muscle relaxation in bronchi, vascular wall,

uterus, insulin and glucagon secretion

4

ENDOCRINOLOGY


• no blood pressure reading over 160/90 mm Hg 24 hours before surgery

• orthostatic hypotension should be present with blood pressure over 80/45 mm Hg

• ECG should be free of ST–T changes for at least 1 week• no more than one ventricular ectopic every 5 min.

Cardiac evaluation: having achieved preoperative cardiac stability, the main determinant of perioperative morbidity is the baseline myocardial status of the patient. The most common effect of phaeo-chromocytoma on the heart is the development of a hypertrophic cardiomyopathy, secondary to chronic noradrenaline-induced hypertension. Less commonly, a dilated cardiomyopathy and subsequent cardiac failure can occur. Therefore, all patients with a phaeochromocytoma should have a preoperative echocardiogram regardless of blood pressure levels. Pathological findings on the ECG are common and these generally improve after aggressive medical treatment and surgery.

Intraoperative managementClose communication between the surgical, endocrine and anaes-thetic teams is necessary for the successful management of patients undergoing phaeochromocytoma resection. Surgical approach – adrenalectomy can be performed using an open lateral retroperitoneal approach or by laparoscopic transperitoneal surgery. The open procedure is quicker and less likely to result in surges of catecholamine release. However, the postoperative period is longer and more painful than the laparo-scopic approach, after which patients can be discharged within 48 hours. Monitoring – preoperative preparation with adrenoceptor antagonists blunts the cardiovascular response to catecholamine surges that occurs secondary to physical manipulation of the tumour. Reliable invasive monitoring of arterial and central venous pressures is essential. Measurement of pulmonary capillary wedge pressure and cardiac output can be helpful because these patients may exhibit a discrepancy between right-sided and left-sided filling pressure, particularly during tumour manipulation. Anaesthesia – general anaesthesia is most commonly used and most anaesthetic agents have been used successfully. The depth of anaesthesia and associated vasodilatation is generally more important than the specific agent. Sevoflurane and isoflurane have been used extensively. Halothane can result in severe arrhythmias with high levels of circulating catecholamines. Desflurane causes significant sympathetic stimulation and is best avoided. Propofol, thiopental and etomidate have all been successfully used for induc-tion. Indirect sympathomimetic agents (e.g. ketamine, ephedrine) can stimulate the tumour to release catecholamines and should be avoided. Drugs that cause histamine release (e.g. morphine, tubocurarine, atracurium) have infrequently been reported to trig-ger a crisis. Hypertension during tumour resection has two distinct aetiolo-gies. Noxious stimuli (e.g. intubation, skin incision, abdominal exploration) cause increased catecholamine release, but use of epidural analgesia (T9–L1), opioid infusions (e.g. remifentanil, alfentanil) and deep anaesthesia can blunt these responses. Tumour manipulation can produce a more marked hypertensive response, associated with significant increases in plasma catecholamine levels, systemic vascular resistance, pulmonary capillary wedge

pressure and occasionally a fall in cardiac output secondary to left ventricular dysfunction. Hypertension secondary to tumour palpation is best treated with systemic vasodilators.• Phentolamine is a competitive α1-adrenoceptor and weak α2-adrenoceptor antagonist that can be given intravenously by infusion or in increments of 1–2 mg. It has a short onset of action (one circulation time) and short duration of action (10–15 min). Side-effects include a tachycardia secondary to presynaptic α2-adrenoceptor blockade.• Sodium nitroprusside is a mixed vaso- and venodilator that reduces preload and afterload. It acts by stimulating the formation of cyclic guanosine monophosphate that relaxes vascular smooth muscle. Its onset is immediate and duration of action 1–2 min. Toxic metabolites, such as cyanide and thiocyanate, can accumulate at infusion rates greater than 2 µg/kg/min.• Magnesium sulphate has several potentially beneficial actions. It has antiarrhythmic properties due to calcium channel block-ade, regulation of intracellular potassium and ATP activation. It causes vasodilatation by blocking the adrenoreceptor response to

General principles of elective phaeochromocytoma surgery

Preoperatively• Determine the tumour location and its pattern of

catecholamine secretion

• Echocardiogram to assess myocardial function ± presence of

cardiomyopathy

• Establish α1-adrenergic blockade to control hypertension

• Add β-blocker to control heart rate or rhythm (especially with

adrenaline secretors)

Perioperatively• Sedative premedication

• Insert invasive arterial monitoring pre-induction

• Obtund pressor response to intubation

• Establish central venous pressure monitoring

• Maintain anaesthesia with moderate degree of vasodilatation

(e.g. isoflurane)

• Ensure adequate surgical analgesia by T9–L1 epidural (open

procedure) or opioid infusion (laparoscopic)

• Treat hypertensive surges during tumour manipulation with

phentolamine, 1–2 mg boluses, or magnesium sulphate

infusion, therapeutic range 2–4 mmol/litre

• Control tachyarrhythmias with β-blockade (e.g. esmolol,

labetalol)

• Predict hypotension in response to clamping of veins draining

tumour

Postoperatively• HDU/ITU care with invasive monitoring

• Aim for early extubation to ensure awake and functioning

reticular activating system

• Use posture and intravenous fluids to maintain blood

pressure; vasopressors can be ineffective

5

ENDOCRINOLOGY


noradrenaline and angiotension II. It also inhibits catecholamine release from the adrenal medulla and peripheral adrenergic nerve terminals. The effective therapeutic plasma concentration is 2–4 mmol/litre which can usually be achieved with an intravenous loading dose of 40–60 mg/kg followed by an infusion of 2 g/hour. Side-effects include a potentiation of neuromuscular blockade and inhibition of platelet activity.• Labetalol is a combined α- and β-adrenoreceptor antagonist. Incremental doses of 5 mg are given to treat surges in blood pres-sure. Used intravenously it causes 7:1 β:α blockade and therefore hypotension and bradycardia can be observed. It is a useful second-line agent to treat adrenaline-induced tachyarrhythmias. Fall in blood pressure – towards the end of the operation, the anaesthetist should anticipate the sudden fall in blood pressure that usually signals the clamping of the final vessels draining the phaeochromocytoma. Ensuring euvolaemia before this, limits the degree of hypotension, though even with central venous pressure monitoring it can be difficult to predict the final volume status of the patient, because the intermittently high catecholamine levels cause marked changes in central venous filling pressures.

Postoperative managementHypotension is the main complication postoperatively and is usually secondary to residual adrenergic blockade. Treatment may be difficult because the hypotension can be refractory to fluid resuscitation and adrenoceptor agonists. Attention to fluid balance and posture are the most effective interventions. Early extubation ensures an awake reticular activating system that helps to maintain blood pressure by stimulating noradrenaline release from sympathetic nerve endings. Catecholamine secretion from the contralateral adrenal gland will have been suppressed by the phaeochromocytoma, and adrenoreceptors will be down-regulated

for some time. If hypotension persists, haemorrhage should be excluded. Postoperative blood glucose monitoring is recommended because hypoglycaemia has been reported (Figure 5).

Emergency presentationPhaeochromocytomas may present unexpectedly during coinci-dental surgery and the mortality is 33–50%. The precipitants of a perioperative catecholamine crisis include anaesthetic drugs (e.g. ephedrine, ketamine, pancuronium, droperidol), inadvertent tumour manipulation during patient positioning or increases in intra-abdominal pressure (e.g. laparoscopy). Their presentation can mimic other potentially catastrophic medical emergencies (e.g. malignant hyperthermia, thyroid storm). If the diagnosis is suspected intraoperatively, all stimulation should be stopped immediately. If the tumour secretes predominantly noradrenaline, systemic hypertension may be accompanied by a baroreceptor-mediated reflex bradycardia. The patient may have signs of exces-sive catecholamine secretion, such as vasoconstriction, piloerection and mydriasis. Myocardial ischaemia may be evident on the ECG and tachyarrhythmias can occur, especially with adrenaline-secreting tumours. Pulmonary oedema may develop as a result of pulmonary capillary vasoconstriction and catecholamine-induced myocardial dysfunction. There is no justification for proceeding with surgical excision of the tumour because mortality is unac-ceptably high without preoperative adrenoreceptor blockade. Control of the cardiovascular system should be attempted using the shorter-acting agents described above and the operation terminated with the minimum of surgical stimulation. The patient should be transferred to ICU and the diagnosis confirmed with 24-hour urinary catecholamine excretion. Adrenoceptor blockade should be introduced gradually and a multidisciplinary plan implemented for the excision of the phaeochromocytoma (Figure 6).

6

Intraoperative presentation and treatment of an unsuspected phaeochromocytoma precipitated by abdominal palpation

1 Pre-induction blood pressure and heart rate. 2 Marked hypotension post-induction that responded to fluid resuscitation. 3 Severe hypertension and ventricular tachycardia following abdominal palpation by surgeon. 4 Operation abandoned and labetalol, 5 mg boluses given (total 40 mg). 5 Patient transferred to ICU – pulmonary artery catheter inserted which showed ↑↑ systemic vascular resistance and ↓ cardiac output. 6 Phentolamine, 2 mg boluses (total 22 mg), with improvement in cardiac indices. 7 Severe hypotensive episodes and ↓ central venous pressure requiring aggressive fluid resuscitation (4 litres over 5 hours). 8 24-hour urine catecholamine analysis demonstrated adrenaline and noradrenaline-secreting tumour. Doxazosin and bisoprolol therapy commenced.

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Recognition and management of phaeochromocytoma